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College of Medicine, Miami, Florida; Heart Disease Prevention Program (Wong), University of .... correlation of NC with BMI and all the other components of. Clin.
Clinical Investigations Neck Circumference Is Not Associated With Subclinical Atherosclerosis in Retired National Football League Players

Address for correspondence: Yashashwi Pokharel, MD 6565 Fannin St., Suite B160 Houston, TX 77030 [email protected]

Yashashwi Pokharel, MD, MSCR; Francisco Y. Macedo, MD, PhD; Vijay Nambi, MD, PhD; Seth S. Martin, MD; Khurram Nasir, MD, MPH; Nathan D. Wong, PhD; Jeffrey Boone, MD, MS; Arthur J. Roberts, MD; Christie M. Ballantyne, MD; Salim S. Virani, MD, PhD Section of Cardiovascular Research, Department of Medicine (Pokharel, Nambi, Ballantyne, Virani), Baylor College of Medicine, Houston, Texas; Center for Cardiovascular Disease Prevention (Pokharel, Nambi, Ballantyne, Virani), Methodist DeBakey Heart and Vascular Center, Houston, Texas; Section of Cardiology (Macedo, Nambi, Ballantyne, Virani), Baylor College of Medicine; Michael E. DeBakey VA Medical Center (Nambi, Virani), Houston, Texas; Johns Hopkins Ciccarone Center for the Prevention of Heart Disease (Martin, Nasir), Baltimore, Maryland; Center for Prevention and Wellness Research (Nasir), Baptist Health Medical Group, Miami Beach, Florida; Baptist Cardiovascular Institute (Nasir), Baptist Health South Florida, Miami, Florida; Department of Epidemiology (Nasir), Robert Stempel College of Public Health, Florida International University, Miami, Florida; Department of Medicine (Nasir), Herbert Wertheim College of Medicine, Miami, Florida; Heart Disease Prevention Program (Wong), University of California, Irvine, Irvine, California; Boone Heart Institute (Boone), Denver, Colorado; Living Heart Foundation (Roberts), Little Silver, New Jersey; Health Policy, Quality and Informatics Program (Virani), Michael E. DeBakey VA Medical Center Health Services Research and Development Center for Innovations, Houston, Texas

Background: Neck circumference (NC) is associated with metabolic syndrome (MetS) in the general population. It is not known if NC is associated with MetS and subclinical atherosclerosis in retired National Football League (NFL) players. Hypothesis: We hypothesized that NC is associated with MetS and subclinical atherosclerosis (assessed as coronary artery calcium [CAC] and carotid artery plaque [CAP]) in retired NFL players. Methods: NC was measured midway between the midcervical spine and midanterior neck in 845 retired NFL players. CAC presence was defined as total CAC score >0. CAP was defined as carotid plaque of at least 50% greater than that of the surrounding vessel wall, with a minimal thickness of at least 1.2 mm on carotid ultrasound. Logistic regression analysis was used for the association of NC with CAC or CAP. Results: Of the participants, 21% had MetS. CAC and CAP were present in 62% and 56%, respectively. Those with MetS had a higher median NC than those without MetS (17 vs 16 inches, P < 0.0001). NC was not associated with the presence of CAC or CAP in an unadjusted model and after adjusting for age, race, and cardiometabolic risk factors (odds ratio [OR]: 1.11, 95% confidence interval [CI]: 0.94–1.31 for CAC; OR: 0.96, 95% CI: 0.82–1.12 for CAP per 1-standard deviation increase in NC [3.8 inches]). The results were similar when the predictor variable was NC indexed to body mass index. Conclusions: In retired NFL players with a high prevalence of CAC and CAP, NC was not associated with coronary or carotid subclinical atherosclerosis. NC may not be the most appropriate risk marker for atherosclerosis.

This work was performed primarily at Baylor College of Medicine, Houston, Texas. The views expressed in this article are those of the authors and do not necessarily represent the views of the Department of Veterans Affairs. ´ Dr. Nambi has had research collaboration with GE/ Tomtec. Dr. Martin is supported by the Pollin Fellowship in Preventive Cardiology, as well as the Marie Josee and Henry R. Kravis endowed fellowship. He is listed as a coinventor on a pending patent filed by Johns Hopkins University on a novel method for low-density lipoprotein cholesterol estimation. Nathan D. Wong, PhD, is a consultant for Re-Engineering Healthcare, Inc. Dr. Ballantyne has received grant/research support (all paid to the institution, not the individual) from Abbott, Amarin, Amgen, Eli Lilly, GlaxoSmithKline, Genentech, Merck, Novartis, Pfizer, Regeneron, Roche, Sanofi-Synthelabo, National Institutes of Health, American Heart Association; is a consultant for Abbott, Aegerion, Amarin, Amgen, Arena, Cerenis, Esperion, Genentech, Genzyme, Kowa, Merck, Novartis, Pfizer, Resverlogix, Regeneron, Roche, Sanofi-Synthelabo; and is on the speakers bureau for Abbott. Dr. Virani is supported by the Department of Veterans Affairs Health Services Research and Development Service Career Development Award and the American Diabetes Association. The authors have no other funding, financial relationships, or conflicts of interest to disclose. Additional Supporting Information may be found in the online version of this article.

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Clin. Cardiol. 37, 7, 402–407 (2014) Published online in Wiley Online Library (wileyonlinelibrary.com) DOI:10.1002/clc.22270 © 2014 Wiley Periodicals, Inc.

Received: December 11, 2013 Accepted with revision: February 7, 2014

Introduction Obesity is present in more than two-thirds of the US population1 and is associated with metabolic syndrome (MetS), atherosclerosis, and possibly an increased risk of myocardial infarction and stroke.1 – 3 Traditionally, obesity is assessed using body mass index (BMI) and waist circumference (WC).4 Neck circumference (NC) has been shown to be associated with cardiometabolic risk in both genders across various ethnicities and age groups in the general population.5 – 16 Some of these studies showed that the association was independent of other measures of adiposity.6,12,14,15 Some have proposed using NC as a novel tool to assess adiposity because of its relative ease of measurement compared with BMI or WC.5 – 10 There are no published studies comparing the association of NC with cardiometabolic risk in retired National Football League (NFL) players. To our knowledge, there is no published study to date assessing the relationship of NC with subclinical atherosclerosis in any population. In prior studies, retired NFL players were shown to have a higher prevalence of MetS17,18 compared with the general population. In addition, given the fact that retired NFL players were physically active during their playing years, it is possible that the MetS seen in these players is distinctly different from that seen in the general population. Therefore, it is not known if NC will have similar association with MetS and subclinical atherosclerosis in retired NFL players. Our aim was therefore to first examine the association of NC with other markers of adiposity such as BMI and WC and with various components of MetS. We also examined whether NC was independently associated with subclinical coronary or carotid atherosclerosis as assessed by coronary artery calcium (CAC) or carotid artery plaque (CAP) in retired NFL players. Methods Study Population A total of 1023 retired NFL players voluntarily participated in health screening exams conducted between September 2007 and November 2009, organized and funded by Player Care Foundation and executed by the Living Heart Foundation and Boone Heart Institute. The study details have been previously described.17 – 22 Retired NFL players were invited through mail or local NFL alumni chapter meetings. Participants provided demographics, and medical and professional career information through a questionnaire. Height, weight, WC and NC, and cuff blood pressure (using the CardioVision automated cuff system) were obtained. Three consecutive seated blood pressure readings were obtained; the first reading was discarded and the mean of the second and third readings was used. BMI was defined as weight (in kilograms) divided by height (in square meters). Waist circumference was measured at the top of the umbilicus in inches. Neck circumference was measured (in inches) midway between the midcervical spine and the midanterior neck. In participants with a pronounced laryngeal prominence (Adam’s apple), the measurement was made just inferior to the prominence.23 MetS was defined as per the National Heart Lung and Blood Institute definition.3 Specifically, MetS was defined as the presence of at least 3 of the following 5

criteria: WC >40 inches, triglycerides (TGs) >150 mg/dL, high-denisity lipoprotein cholesterol (HDL-C) 0. CAP Measurement Apart from CAC, we also evaluated CAP as a marker for the presence of subclinical atherosclerosis. CAP is also a wellvalidated measure of subclinical atherosclerosis,32 – 34 and its presence has shown to be associated with an increase risk of cardiovascular events.33 – 36 Ultrasound examination of the carotid artery was performed using a standardized protocol with a Siemens Sequoia or CV70 system (Siemens Healthcare, Erlangen, Germany), with 6- to 8-MHz linear array transducer imaging in longitudinal and transverse planes, visualizing the common carotid artery, carotid bulb, and proximal internal carotid arteries bilaterally. Sonographers were instructed to obtain 3-beat cine images of any suspected plaque along with Doppler imaging of any suspected stenosis. Carotid artery plaque was defined as the presence of focal thickening 50% greater than that of the surrounding vessel wall, with a minimal thickness of 1.2 mm.22 Statistical Analysis Descriptive statistics were evaluated for each variable. We then performed bivariable analysis using a 2-sample Wilcoxon rank sum test for continuous variables and Pearson χ2 test for categorical variables. We also evaluated the Spearman correlation coefficient to assess the linear correlation of NC with BMI and all the other components of Clin. Cardiol. 37, 7, 402–407 (2014) Y. Pokharel et al: Atherosclerosis in retired NFL players Published online in Wiley Online Library (wileyonlinelibrary.com) DOI:10.1002/clc.22270 © 2014 Wiley Periodicals, Inc.

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MetS. Our primary outcomes of interest were the presence of CAC or CAP. Logistic regression was used to calculate the odds ratio (OR) and associated 95% confidence interval (CI) per standard deviation (SD) increase in NC for the presence of CAC or CAP. An initial unadjusted model was first used to determine the association between NC and presence of CAC or CAP. Subsequently, we adjusted for other variables in 2 separate models. In model 1, we adjusted for age, race, SBP, and hs-CRP. In model 2, we adjusted for all the variables from model 1 plus other variables that form part of the MetS (TG, HDL-C, and fasting blood glucose levels). To further examine the association between NC and subclinical atherosclerosis, we also performed sensitivity analyses by indexing NC to BMI defined by NC/BMI for each participant. This variable was created to provide a standardized measure of NC designed to reflect local neck habitus relative to the overall body habitus. BMI was used in this variable because BMI incorporates height and weight, both of which could be related to NC. We also modeled using the exposure variable as NC >90th percentile for association of subclinical atherosclerosis, based on methods used in a prior published study.15 Among those retired NFL players with a CAC score >0, we also assessed whether NC was associated with CAC burden using the natural log of CAC as the outcome variable (ie, ln[CAC + 1]) using linear regression models. All analyses were performed using Stata 12 (StataCorp, College Station, TX). All inferences were 2-tailed, and a P value 90th percentile as the exposure variable, there was no significant association for the presence of CAC or CAP in partially or fully adjusted models, except for the presence of CAC when adjusted for age, race, SBP, and hs-CRP (OR: 1.87, 95% CI: 1.02-3.42). Stratified analysis by the presence or absence of MetS did not change our result in either group (see Supporting Tables 1 and 2 in the online version of this article). Among retired NFL players with CAC >0, NC was not associated with CAC burden (β coefficient = −1.05 and P = 0.24 per SD increase in NC) when adjusted for age, race, SBP, hs-CRP, TGs, HDL-C, and fasting blood glucose.

Discussion In this study of 845 retired NFL players, NC was highly correlated with WC and BMI. NC was positively correlated with all the components of MetS, expect for HDL-C, where the correlation was negative. Retired NFL players with MetS had a thicker NC than those without MetS. NC or NC/BMI had no association with CAC or CAP in unadjusted or adjusted models. NC has been shown to be associated with MetS and its components in studies from various populations such as predominantly young African American females,5 middle-aged Caucasians,14 middle-aged to elderly Chinese,6,16 Israelis,8 Brazilian men and women,9,11 Turkish children, and Greeks.12 Some of these studies have shown that the association is independent of other measures of obesity such as BMI or WC.6,12,14,15 It is likely that NC tracks with obesity because of its consistent correlation with BMI or WC in all of these studies, including ours. This hypothesis is further supported by the consistent correlation of NC with MetS and its components in studies from different populations. We did not have data to assess the prevalence of cardiovascular risk factors and MetS in these NFL players while they were actively playing in the NFL. In addition, there is paucity of data in the literature comparing risk factors in the general population with elite NFL players during their playing years. In cross-sectional analyses, it has been shown that retired NFL players have a higher prevalence of MetS compared to the general population.18,19 Retired NFL players have been physically active for a good part of their lives. Therefore, it can be speculated that the progression of cardiovascular risk factors and the MetS seen in retired NFL players could be distinctly different compared to the general population who have relatively sedentary lifestyle throughout their lives. To our knowledge, ours is the first study examining the association of NC with subclinical atherosclerosis in any population. We measured subclinical atherosclerosis at 2 separate vascular sites. NC did not have significant association with subclinical coronary or carotid atherosclerosis, despite the higher prevalence of CAC and CAP in the study population. It is possible that increased NC in retired NFL players may be relatively less reflective of adiposity compared to the general population. Increased NC in this population could reflect a higher than usual contribution from neck muscle given their background of weight lifting and training during their professional years. There are only a few studies that evaluated the association of NC with adverse cardiovascular outcomes. In a Clin. Cardiol. 37, 7, 402–407 (2014) Y. Pokharel et al: Atherosclerosis in retired NFL players Published online in Wiley Online Library (wileyonlinelibrary.com) DOI:10.1002/clc.22270 © 2014 Wiley Periodicals, Inc.

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case–control study of 376 Brazilians referred for elective coronary angiogram, NC above the 90th percentile was significantly associated with at least 50% coronary stenosis after controlling for traditional risk factors of coronary artery disease.15 In 3086 participants from the Framingham Heart Study, despite having a significant correlation with all the risk factors for MetS, NC was not significantly associated with an increase in incident cardiovascular disease or coronary heart disease after a mean 6.7 years of follow-up in an adjusted model.14 There was also no significant interaction of NC with gender for these outcomes. The paradox on the consistent association of NC with MetS, but not with cardiac outcomes from the limited available studies, should be answered by longitudinal welldesigned studies to examine if there is any biological reason for this observation or if this is a result of methodological limitations of the currently available studies. It is also not known if the lack of association of NC with subclinical atherosclerosis is unique to our study population, which has overall higher prevalence of MetS and higher BMI and unique body habitus, or applicable to the general population. Further research should inform us if similar lack of association exists in athletes involved in different kinds of sports (eg, athletes involved in rugby football) or persons with similar body habitus from various populations. It must be emphasized that although NC was not associated with subclinical atherosclerosis in our study, NC could still play a role in the pathogenesis of other cardiovascular disorders such as obstructive sleep apnea in this population. Our study has limitations. Because the retired NFL players’ participation in the study was on a voluntary basis, the possibility of selection bias cannot be excluded. Our study was limited to subclinical atherosclerosis and not to hard cardiovascular outcomes. Our study participants were all male and consisted mainly of Americans of European descent and African Americans. We did not have information on other possible confounders such as smoking status and treatment of other risk factors. Moreover, our study was cross-sectional in design, and therefore the findings are only hypothesis generating.

Conclusion Although NC was correlated with MetS and its components, it was not associated with coronary or carotid subclinical atherosclerosis in retired NFL players with a high prevalence of CAC and CAP. Acknowledgments The authors thank the retired NFL players who participated in this study.

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Clin. Cardiol. 37, 7, 402–407 (2014) Y. Pokharel et al: Atherosclerosis in retired NFL players Published online in Wiley Online Library (wileyonlinelibrary.com) DOI:10.1002/clc.22270 © 2014 Wiley Periodicals, Inc.

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